(Circulation. 1998;97:937.)
© 1998 American Heart Association, Inc.
Does 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor Therapy Exert a Direct Anti-Ischemic Effect?
Pericle Di Napoli, MD;
; Prof Antonio Barsotti, MD
Istituto di Clinica Cardiovascolare,
Università degli Studi G. D'Annunzio,
Chieti, Italy
To the Editor:
We read with great interest the recent well-written article by Andrews
et al1 in Circulation, and we would
like to add a comment to the editorial observation of Dr
Frye.2
The most important finding of the study is that in selected patients
with documented coronary artery disease associated with
myocardial ischemia on ambulatory ECG monitoring, dietary
treatment and lovastatin therapy induced, after 4 to 6
months, a significant reduction of ischemic events compared
with the control group (dietary treatment). Andrews et
al1 concluded that the importance of their study
is the evidence that cholesterol lowering is related to
clinical manifestations of coronary artery disease and reduces
cardiac events in the medium term.
Two points we would consider in the discussion of these results:
(1) In long-term follow-up, several clinical
studies3 4 reported that cholesterol
lowering results in an improvement of prognosis or coronary
atheroma regression.
(2) Clinical and experimental data5 6 suggest
that hypercholesterolemia affects
endothelial function (abnormal constriction provoked by
acetylcholine, reduction of endothelial nitric oxide
production), but the time course of these alterations is still
unknown.
In our opinion, the positive effects of statin therapy on myocardial
ischemia may also be related to 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibition rather than only to the total
and LDL cholesterol reduction. This hypothesis, at least in
part, is supported by the evidence of best result, regarding mortality
and ischemic events, obtained by statin therapy with respect to
dietary treatment or therapy with fibrates.
We think that an important role in myocardial ischemia
reduction and long-term prognosis improvement during HMG-CoA reductase
inhibitor therapy may be due to a direct
anti-ischemic effect of statin therapy, which potentially also
provides a benefit during acute ischemia. In isolated working
hearts of normolipidemic rats subjected to 15 minutes of global
ischemia, our preliminary data suggest that short-term
administration of simvastatin (50 µM) induces a
significant reduction in ischemia-reperfusion damage and
coronary endothelium dysfunction
(endothelial permeability). At this time, we have no
definitive data regarding the mechanism of this acute protective effect
(reduction of postischemic coronary permeability
changes via nitric oxide production or local modulation of
coronary arterial tone?), but our observation, if
not definitive evidence of a direct anti-ischemic effect of
statins, suggests that further investigation is needed and may
contribute to providing an explanation of the positive effects of
statin therapy in short-term follow-up, which positive effect
paradoxically also occurs in ischemic patients with normal
total and LDL cholesterol.
References
1.
Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P,
Selwyn AP. Effect of cholesterol reduction on myocardial
ischemia in patients with coronary disease.
Circulation. 1997;95:324–328.[Abstract/Free Full Text]
2.
Frye RL. Clinical reality of lowering total and LDL
cholesterol. Circulation. 1997;95:306–307.[Free Full Text]
3.
Scandinavian Simvastatin Survival Study Group.
Randomized trial of cholesterol lowering in 4444 patients
with coronary artery disease: the Scandinavian
Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.[Medline]
[Order article via Infotrieve]
4.
Pitt B, Mancini GB, Ellis SG, Rosman HS, Park JS, McGovern ME.
Pravastatin limitation of atherosclerosis
in the coronary arteries (PLAC 1): reduction in
atherosclerosis progression and clinical events—PLAC 1
investigation. J Am Coll Cardiol. 1995;26:1133–1139.[Abstract]
5.
Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME,
Kosinski AS, Zhang J, Boccuzzi SJ, Cedarholm C, Alendander RW.
Beneficial effects of cholesterol-lowering therapy on the
coronary endothelium in patients with
coronary artery disease. N Engl J Med. 1995;332:481–487.[Abstract/Free Full Text]
6.
van Boven AJ, Jukema W, Zwinderman AH, Crijns HJ, Lie KI,
Bruschke AVG. Reduction of transient myocardial ischemia with
pravastatin in addition to the conventional treatment in
patients with angina pectoris. Circulation. 1996;94:1503–1505.[Abstract/Free Full Text]
